Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common Mendelian disorders in humans affecting 1/1000 worldwide. The hallmark of the disease is the development of multiple cysts from renal tubules in both kidneys, resulting in end-stage renal failure in 50% of the patients. ADPKD is a systemic disease with many ex-renal manifestations. Since the PKD1 gene was identified in 1995, significant efforts have been made in understanding of the biology underlying the disease. But the normal function its gene product, polycystin-1, is still poorly understood. The question of how a mutation in the single PKD1 gene leads to a vast array of defects is also unresolved. The long-term goal of our research is to understand the normal biological function of polycystin-1 during the development and its role in the maintenance of adult organs, and the mechanisms by which PKD1 mutations cause the disease. Post-translational modifications of the protein are known to play a critical role for its activity and such processes have been implicated for the function of polycystin-1. We have found that polycystin-1 undergoes proteolyctic cleavage in vivo. Our preliminary results have indicated that this type of the post-translational processes is likely important for the functionality of polycystin-1. In the grant application, we propose to investigate the role of the proteolytic cleavage of polycystin-1 using a combination of chemical, biochemical, genetic and cell biological approaches. We plan to examine the functional significance of this process in the cell culture system and in the mouse. Furthermore, we propose to characterize the mechanism of regulation of the cleavage reaction and analyze the cellular machinery of the process. This scientific query will likely provide important insights into the functions and novel mechanism of the regulation of potycystin-1. Our investigation will also likely provide clues of the mechanisms by which PKD1 mutations cause the disease. The information from our studies will likely open new avenues in the research of ADPKD and establish the foundation for developing causative and effective therapies of the disease.